The long-term goals of this research are an understanding of neurobehavioral mechanisms determining the addictive liabilities of drugs and the rational development of pharmacotherapies that will act on these mechanisms to reduce or eliminate addictive behavior. Recent research in this laboratory has focused on dopamine pathways as sites of opioid and stimulant drug actions, on the neurochemical basis for individual differences among rats in opioid and stimulant self-administration, and on the behavioral and neurochemical effects of ibogaine, a putative anti- addictive agent. The studies proposed now will focus exclusively on the neuropharmacology of ibogaine and related drugs and their interactions with opioid and stimulant drugs of abuse. The methodology uses rats and involves measurement of intravenous drug self-administration and of drug effects on motor activity and brain chemistry. In vivo microdialysis combined with HPLC (high performance liquid chromatography) is used to assay extra-cellular levels of biogenic amines (dopamine, norepinephrine, serotonin) and their metabolites in discrete brain regions. Specific experimental problems include the following: (1) The effects of ibogaine and ibogaine congeners on morphine and cocaine self-administration will be investigated, and an agent will be sought that is more potent than ibogaine in suppressing drug self-administration but less potent than ibogaine in producing motor side effects (e.g., tremors). The role of prior drug (morphine or cocaine) exposure in determining subsequent drug interactions with ibogaine will be examined; it is hypothesized that variable effects of ibogaine on drug self-administration may be attributable to variable histories of drug exposure. (2) Neurochemical mechanisms that might mediate the effects of ibogaine and related alkaloids on drug self-administration will be studied. In vivo microdialysis will be used to characterize the neurochemical actions of iboga alkaloids and to localize their neuroanatomical sites of interactions with opioids and stimulants. The hypothesis will be tested that prior exposure to morphine, and possibly other drugs, sensitizes rats to the neurochemical actions of ibogaine. (3) Metabolic mechanisms of ibogaine's interactions with opioids and stimulants will be studied; it is hypothesized that long-term effects of ibogaine are mediated by persistent low levels of ibogaine in brain and/or by active metabolites of ibogaine. GCMS (gas chromatography-mass spectrometry) will be used to study the disposition and metabolism of ibogaine, and to determine the effects of ibogaine and other iboga alkaloids on brain levels of morphine, cocaine and d-amphetamine. This research, which should provide basic information concerning neurobiological approaches to reducing drug self- administration, may result in novel treatments for addictive disorders in humans.